The objective of this study is the genetic analysis of gene expression as a phenotype in humans. The overall goals are to measure gene expression and characterize its variation in human cells, and to identify the genetic determinants of this variation. The specific aims for this renewal application are: 1) Determine the gene expression phenotypes of individuals in the CEPH families, 2) Map the determinants of variation in gene expression for several thousand genes, and 3) Identify and characterize the genetic determinants of variation in gene expression. In the last two years, we have identified a set of genes whose expression levels vary among unrelated individuals, and shown that there is a genetic component to this variation. In this renewal application, we will first complete the expression phenotyping of individuals in 59 families. Using the SNP genotypes for the same individuals, we will map the genetic determinants of the expression phenotypes by genome-wide linkage analysis and TDT methods (for fine mapping by linkage disequilibrium). Once we have identified candidate regions, we will identify the transcriptional regulators and functional variants in these regions using a combination of computational and molecular techniques. We expect to identify the gene and gene products involved in the complex network of transcriptional regulation, and to begin to describe the relationship between them. The approaches used in this project will allow us to understand better how transcription is regulated and to integrate genome variation at the level of RNA expression with that at the DNA sequence level. This work also has important implications for human disease, since some polymorphic variants that affect gene expression level are associated with disease susceptibility. [unreadable] [unreadable]